Targeting Polo-Like Kinase 1 in Prostate Cancer to Enhance Therapeutic Efficacy

靶向前列腺癌中的 Polo 样激酶 1 以增强治疗效果

基本信息

批准号：
10650837
负责人：
Zhiguo Li
金额：
$ 43.63万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10650837
关键词：
Alleles Androgens Apoptosis Autophagocytosis Biometry Breeding Cancer Etiology Cancer Patient Cell Survival Cells Cellular biology Cessation of life Clinic Clinical Research Creativeness Data Disease Enterobacteria phage P1 Cre recombinase Fostering Genetically Engineered Mouse Goals Health Immune checkpoint inhibitor Immunocompetent Immunosuppression Immunotherapy Infiltration Investigation Lymphocyte Malignant Neoplasms Malignant neoplasm of prostate Measurement Mediating Membrane Mission Molecular Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Oncology Outcome Oxidative Stress PDL1 inhibitors PDL1 pathway PLK1 gene Pathology Patient-Focused Outcomes Patients Phosphorylation Phosphotransferases Play Prognosis Proliferating Prostate Cancer therapy Public Health Reactive Oxygen Species Refractory Regulation Research Residual state Role Signal Pathway Signal Transduction Survival Rate Testing Therapeutic Therapeutic Agents Therapeutic Effect Treatment Efficacy Tumor Escape Tumor Immunity Tumor-infiltrating immune cells Up-Regulation Work advanced prostate cancer androgen deprivation therapy anti-PD-L1 therapy cancer cell castration resistant prostate cancer cell growth comparative efficacy design effective therapy immune cell infiltrate improved inhibitor innovation men mortality mouse model neoplastic cell novel novel strategies novel therapeutic intervention nuclear factor-erythroid 2 pharmacologic programmed cell death ligand 1 programs promoter prostate cancer cell prostate cancer progression receptor response synergism targeted treatment therapeutically effective tumor tumor growth tumor microenvironment tumor xenograft tumor-immune system interactions

项目摘要

Title: Targeting Polo-like kinase 1 in prostate cancer to enhance therapeutic efficacy Abstract Prostate cancer (PCa) is the second most common cause of cancer death in men in the US. Over the past several decades, androgen deprivation therapy has been the primary therapeutic option for patients with advanced PCa; however, the majority of patients developed into a poor prognosis stage of castration-resistant prostate cancer (CRPC), which eventually led to mortality. And the current therapeutic agents for CRPC patients only extend survival by around 2.5 - 5 months. Therefore, novel and effective therapeutic strategies for CRPC patients are urgently needed. The long-term goals of this study are to identify druggable signaling pathways that offer more effective treatment options for patients with CRPC. The objective is to identify the role of Plk1/p62/Nrf2 signaling pathway in CRPC, and to exploit the potentially therapeutic strategies that could be benefit the CRPC patients. The central hypothesis is that Nrf2 is activated by a noncanonical mechanism involving p62 phosphorylation by Plk1 in CRPC. Our hypothesis will be tested by pursuing Three Specific Aims: (1) to determine the novel role of Plk1 as regulator of cellular response to oxidative stress. (2) examine the role of Plk1/p62/Nrf2 axis in tumor growth in mouse models. And (3) whether inhibition of Plk1/p62/Nrf2 signaling pathway enhance the efficacy of CRPC therapy. The expected results will reveal a novel molecular mechanism to show how Plk1 contributes to PCa progress, and will open up new avenues for application of Plk1 inhibitors as a therapeutic option. The team, with expertise in Plk1 in mouse models, Plk1 in cancer cell biology, PCa pathology, GU oncology and biostatistics, will be able to finish the proposed research in a timely manner.

标题：靶向前列腺癌中的 Polo 样激酶 1 以增强治疗效果抽象的前列腺癌 (PCa) 是美国男性癌症死亡的第二大常见原因。过去的事几十年来，雄激素剥夺疗法一直是患有以下疾病的患者的主要治疗选择高级前列腺癌；然而，大多数患者发展为去势抵抗的预后不良阶段前列腺癌（CRPC），最终导致死亡。以及目前CRPC的治疗药物患者的生存期仅延长约 2.5 - 5 个月。因此，新的、有效的治疗策略 CRPC患者急需。这项研究的长期目标是确定可药物信号传导为 CRPC 患者提供更有效的治疗选择。目标是确定角色 CRPC 中 Plk1/p62/Nrf2 信号通路的研究，并探索潜在的治疗策略造福CRPC患者。中心假设是 Nrf2 是由非规范机制激活的涉及 CRPC 中 Plk1 的 p62 磷酸化。我们的假设将通过追求三个具体目标来检验： (1) 确定 Plk1 作为细胞氧化应激反应调节剂的新作用。 (2)考察角色 Plk1/p62/Nrf2 轴在小鼠模型肿瘤生长中的作用。 (3)是否抑制Plk1/p62/Nrf2信号传导途径增强CRPC治疗的疗效。预期结果将揭示一种新的分子机制展示Plk1如何促进PCa进展，并将为Plk1抑制剂的应用开辟新途径作为一种治疗选择。该团队在小鼠模型中的 Plk1、癌细胞生物学中的 Plk1、PCa 方面拥有专业知识病理学、GU肿瘤学和生物统计学，将能够及时完成拟议的研究。